Introduction vasopressin

The first non-peptide oxytocin antagonists, based on a spiropiperidine template, were described by Merck in 1992 [68-70]. The binding affinity data for key compounds from this series are summarised in Table 7.2. The initial screening hit, L-342,643, (23), had modest (4/iM) affinity for rat uterine oxytocin receptors and very little vasopressin selectivity [71]. A structure activity relationship (SAR) study was carried out around this template, focussing on the toluenesulphonamide group. This work led to the identification of bulky lipophilic substitution as key to improved oxytocin potency, while the introduction of a carboxylic acid group led to improved... 

The Maillard reaction is likely to take on additional significance with the introduction of many new protein and peptide pharmaceuticals. For example, Tarelli et al. have demonstrated that lysine vasopressin undergoes rapid glycation in the presence of reducing sugars in both aqueous and solid formulations and that the N-terminal adduct can form rapidly even at — 20°C [52], A textbook that deals with the consequences for the chemical and life sciences of the Maillard reaction has been published [53]. 

Before the introduction of specific vasopressin receptor antagonists, pharmacological treatments for hyponatremia centered on the use of loop diuretics and nonspecific inhibitors of vasopressin signaling, such as lithium carbonate and demeclocycline.11 The utility of such therapies has been limited by a range of sideeffects. Loop diuretic use can result in electrolyte imbalances and suffers from poor response predictability.11 Lithium carbonate suffers from a low therapeutic index and a risk of renal damage as well as limited effectiveness in many patients. Lithium carbonate has therefore been nearly completely supplanted by demeclocycline, a tetracycline antibiotic, in the treatment of chronic hyponatremia.12 Demeclocycline use is itself limited by its nephrotoxicity (particularly in cirrhotic patients), ability to cause reversible uremia, and ability to induce photosensitivity.1,11... 

Pituitary glands are incubated in tissue culture medium and TSH measured in the medium after introduction of the TRF. The presence of calcium in the medium is necessary (VI). TSH is measured either by bioassay or more recently by radioimmunoassay (W2). In vitro methods require only a few rat pituitary glands, and incubation times are short. TSH release into the medium is a linear fimction of the log dose (GIO). Crude hypothalamic extracts can be assayed in this way, since contaminating vasopressin does not stimulate TSH release from the pituitary (R2). This latter point has been recently questioned, however, by Krass et al. (K5). Vasopressin may stimulate TSH release in vitro. 

Position 8. Variations in position 8 of the vasopressins are found in nature in this respect, there are analogies with the oxytocin series. Lysine-vasopressin occurs in the pig, the hippopotamus and the peccary. Introduction of leucine yields oxypressin (Leu -vasopressin = Phe -oxytocin) which has activities intermediate between oxytocin and vasopressin. Introduction of D-amino acids yields compounds with low pressor activity but high antidiuretic activity. 

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